In Japan, about 40,000 people are thought to die of acute myocardial infarction each year. In the United States, it is estimated that about 1.5 million people develop myocardial infarction every year, and among them, the number of deaths is about 600,000. Acute myocardial infarction is a disease in which the coronary artery is occluded by, for example, thrombosis, and blood flow to the myocardium under the coronary artery is obstructed, leading to myocardial necrosis. Therefore, acute myocardial infarction is treated through a therapy in which blood flow is restored by recanalization of the occluded coronary artery, together with treatment of arrhythmia, such as ventricular fibrillation (hereinafter the therapy may be referred to as “myocardial ischemia-reperfusion therapy”). Myocardial ischemia-reperfusion therapies include a thrombolytic therapy using, for example, t-PA, and PTCA using a balloon catheter. When such a myocardial ischemia-reperfusion therapy is performed within six hours after the onset of myocardial infarction, the therapy achieves high survival rate and is effective.
However, it has been known that myocardial ischemia-reperfusion causes inflammatory response due to, for example, free radicals (e.g., active oxygen), vascular endothelial cell injury, or neutrophil activation, resulting in additional damage to the myocardium. Thus, demand has arisen for development of a drug that reduces the incidence of myocardial ischemia-reperfusion injury.
Adenosine is known as a compound that reduces the incidence of myocardial ischemia-reperfusion injury (see Non-Patent Document 1). Exogenous adenosine increases coronary blood flow via the A2 receptor, and inhibits generation of free radicals from activated neutrophils. In addition, exogenous adenosine activates the A1 receptor, thereby suppressing an increase in adrenergic-β-receptor-mediated myocardial contractility, an increase in amount of Ca2+ influx into the myocardium, or an increase in amount of released norepinephrine. By virtue of these effects, adenosine suppresses myocardial injury caused by myocardial ischemia, or myocardial ischemia-reperfusion injury.
However, adenosine has a short half life (<10 sec) in blood, and thus exhibits a short duration of action. Therefore, expression of the myocardial protection effect of adenosine through peripheral intravenous injection requires administration of a large amount of adenosine for a long period of time (30 minutes to 1 hour) (see Non-Patent Document 2). Meanwhile, adenosine is known to cause side effects such as lowered blood pressure or heart rate. Such adverse effects of adenosine on hemodynamics through administration thereof to a myocardial infarction patient are not desired.
At present, adenosine is used in clinical practice as a diagnostic aid for cardiac diseases (see Non-Patent Document 3).
Non-Patent Document 1: Drug Development Research, vol. 28, 432-437, 1993
Non-Patent Document 2: J. Am. Coll. Cardiol., 1775-1780, 2005
Non-Patent Document 3: JAPIC Iryo-yo Iyakuhin-shu (Data on Drugs for Medical Use) 2007, edited and published by Japan Pharmaceutical Information Center, Sep. 1, 2006, pp. 88-90